Creams containing vitamin D3 derivatives

ABSTRACT

An O/W cream contains maxacalcitol as an active ingredient. The maxacalcitol is present in both the oil phase and in the water phase of the cream.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application is a continuation of application Ser. No.10/612,109, filed Jun. 5, 2002, which is the continuation of Ser. No.09/555,814, filed Jun. 5, 2000, which is the national stage under 35U.S.C. 371 of PCT/JP98/05536, filed Dec. 8, 1998.

FIELD OF THE INVENTION

[0002] The present invention relates to O/W type creams for skinapplication, which creams exhibit improved skin transfer andphysical/chemical stability of maxacalcitol as an active ingredient,more specifically, the present invention relates to O/W type creams inwhich maxacalcitol as an active ingredient exists in the oil phaseand/or water phase.

BACKGROUND ART

[0003] Some classes of vitamin D₃ derivatives such as1α,3β-dihydroxy-20α-(3-hydroxy-3-methylbutyloxy)-9,10-seco-5,7,10(19)-pregnatriene(22-oxa-1α,25-dihydroxyvitamin D₃; herein also referred to asmaxacalcitol) have been reported to have epidermal cellgrowth-inhibiting and differentiation-inducing effects and to be usefulas antipsoriatics (JPA Nos. 267550/86 and 183534/88). In development ofdosage forms of antisporiatics, preparations for topical application arethought to be preferable because the target site of antipsoriatictherapy is epidermal cells.

[0004] However, no formulation for topical application containingmaxacalcitol as an active ingredient and having excellent performancehas been reported to date.

DISCLOSURE OF THE INVENTION

[0005] Preparations for topical application may be presented in suchdosage forms as ointments, creams or lotions. Dosage forms vary with theapplication site. Ointments are applied over the whole body, especiallyunder clothing. Creams are applied on parts exposed to the air such asthe face or the hands, and lotions are applided to the scalp or thelike. Especially, creams which are exposed to the air are required tohave benefits such as non-tackiness after application and inconspicuousappearance at the treated site.

[0006] In the development of creams as one dosage form for topicalapplication, O/W type creams containing a large amount of water in anouter water phase are thought to be most advantageous for seeking suchbenefits as non-tackiness after application and inconspicuous appearanceat the treated site. O/W type creams containing maxacalcitol as anactive ingredient may include two types, depending on whether the activeingredient exists in the oil phase or the water phase.

[0007] Maxacalcitol is known to be slightly soluble in water and to beunstable in aqueous solutions; it is also known to be highly soluble andhave dramatically improved stability in organic solvents such as ethanoland chloroform and also to have very high stability in base materialssuch as petrolatum. Therefore, O/W type creams containing maxacalcitolin an inner oil phase have been supposed to be preferable formaintaining an advantageous creamy form and for stably containing theactive ingredient maxacalcitol.

[0008] However, it is also important in development of creams to ensurechemical stability of the active ingredient, as well as physicalstability of the emulsion. It is regarded that the physical stability ofthe emulsion depends on the concentrations of surfactants andco-surfactants; as both concentrations become higher and as the ratio ofthe concentrations becomes closer to a proper value, more stableemulsification is achieved.

[0009] As for the skin absorption of the active ingredient, thefollowing are regarded as contributing to low skin absorption of theactive ingredient:

[0010] 1) high affinity of maxacalcitol for the oil phase base material,2) low delivery or access rate of oil phase to skin, and 3) inhibitionrelease of the maxacalcitol from the oil phase during transfer ofmaxacalcitol to skin. More specifically, transfer of maxacalcitol toskin may be inhibited by the presence of surfactants and co-surfactantsat the oil/water interface or the presence of crystalline structuresaround oil-phase particles. Namely, when a drug is contained in theinner oil phase, the surfactant phase existing at the oil/waterinterface or the crystalline structures existing around the oil-phaseparticles during the release process may further hinder the release ofthe drug.

[0011] In order to eliminate the above disadvantages and enhance skintransfer by removing rate-limiting factors during the release process,we tried to develop a cream containing the drug maxacalcitol in theouter water phase and concurrently a cream containing maxacalcitol inthe oil phase.

[0012] As described above, an object of the present invention is toprovide a cream maintaining a creamy form, showing high skin absorptionof the active ingredient maxacalcitol and stably maintaining said activeingredient for a long time-period.

[0013] As a result of careful studies conducted to find a cream showinghigh skin absorption of the active ingredient maxacalcitol and stablymaintaining said active ingredient for a long time-period, we obtainedthe following finding. In O/W type creams wherein maxacalcitol exists inthe oil phase, stability of the emulsion dramatically improved, howeverthe skin transfer rate of the active ingredient decreased when theconcentrations of surfactants and co-surfactants increased. In order toincrease the skin transfer rate, it seemed necessary to decrease thosefactors which are regarded to be responsible for the absorptioninhibition, in other words, the amount of surfactants existing at theoil/water interface or the amount of crystalline structures producedaround oil-phase particles. Thus, we attempted to decrease the loadingof surfactants and co-surfactants in so far as a stable emulsion wouldbe maintained. As a result, we found that an excellent cream is providedwhen the total concentration of surfactants and co-surfactants in thecream is within the range of from 2 to 7% by weight. We also found thatabsorption can be controlled by incorporation of maxacalcitol in the oilphase, whereby an optimal level in skin can be maintained. A part of thepresent invention was accomplished on the basis of these findings.

[0014] As a result of careful studies to improve the skin absorption andthe storage stability of creams containing maxacalcitol in the waterphase, we also found that a homogeneous dispersion of maxacalcitol inthe outer water phase ensures the storage stability of maxacalcitol andalso remarkably improves the skin absorption to approximately twice ascompared with creams containing maxacalcitol in the inner oil phase. Apart of the present invention was accomplished on the basis of thesefindings.

[0015] As described above, we accomplished the present invention on thebasis of the findings that incorporating maxacalcitol in the water phasecan remarkably improve absorption and that incorporating maxacacitol inthe oil phase can control absorption.

[0016] Moreover, we also found that the maxacalcitol level in skin canbe controlled over a wide range, from low to high levels, byincorporation of maxacalcitol in both of oil and water phases.

[0017] Accordingly, the present invention provides an O/W type creamcontaining maxacalcitol in the oil phase and/or water phase.

[0018] According to an aspect of the present invention, there isprovided an O/W type cream containing maxacalcitol and an emulsifier,wherein maxacalcitol exists in the oil phase.

[0019] In creams of the present invention, the emulsifier is preferablya mixture of a surfactant and a co-surfactant.

[0020] In creams of the present invention, the ratio between surfactantsand co-surfactants is preferably within the range of from 1:1 to 1:11.

[0021] In creams of the present invention, the total concentration ofsurfactants and co-surfactants in a cream is preferably within the rangeof from 2 to 7% by weight.

[0022] In creams of the present invention, the surfactant is preferablyan ether-type surfactant.

[0023] In creams of the present invention, the surfactant is morepreferably a polyoxyethylene alkyl ether.

[0024] In creams of the present invention, the co-surfactant ispreferably a higher alcohol.

[0025] In creams of the present invention, the co-surfactant is morepreferably stearyl alcohol, cetyl alcohol or cetostearyl alcohol.

[0026] In creams of the present invention, the ratio of oil phase in anO/W type cream is preferably within the range of from 30 to 50% byweight.

[0027] According to another aspect of the present invention, there isprovided an O/W type cream, wherein maxacalcitol exists in the waterphase.

[0028] According to an embodiment of the O/W type cream whereinmaxacacitol exists in the water phase, there is provided an O/W creamwherein crystalline maxacalcitol is pulverized and contained in thewater phase.

[0029] According to another embodiment of the O/W type cream whereinmaxacalcitol exists in the water phase, there is provided an O/W creamwherein crystalline maxacalcitol is dissolved in an organic solvent andcontained in the water phase.

[0030] According to still another embodiment of the O/W type creamwherein maxacalcitol exists in the water phase, there is provided an O/Wcream containing an alcohol and/or a nonionic surfactant in the waterphase.

BRIEF DESCRIPTION OF THE DRAWING

[0031]FIG. 1 is a graph showing the relationship between theconcentration of cetostearyl alcohol and skin transfer rate of creams ofthe present invention wherein maxacalcitol exists in the oil phase.

PREFERRED EMBODIMENTS OF THE INVENTION

[0032] The present invention relates to O/W type creams whereinmaxacalcitol exists in the oil phase and/or water phase.

[0033]1α,3β-Dihydroxy-20α-(3-hydroxy-3-methylbutyloxy)-9,10-seco-5,7,10(19)-pregnatriene(22-oxa-1α,25-dihydroxyvitamin D₃; herein also referred to asmaxacalcitol) contained in cream of the present invention as an activeingredient is a known vitamin D₃ derivative and can be synthesized bythe process described in JP No. 267550/86, for example.

[0034] The amount of maxacalcitol contained in creams of the presentinvention is a therapeutically effective amount for the skin disease tobe treated, normally within the range of from about 1 μg/g to about 200μg/g, preferably about 2 μg/g to about 100 μg/g.

[0035] Creams of the present invention include three embodiments whereinmaxacalcitol exists in the oil phase, water phase or both. The first twoembodiments wherein maxacalcitol exists in the oil phase or the waterphase are specifically described below, but it should be understood thatthe following description is also applicable to the case wheremaxacalcitol exists in both oil and water phases.

[0036] (1) Maxacalcitol Exists in the Oil Phase:

[0037] Surfactants suitable for creams of the present inventionpreferably include ether-type surfactants, especially polyoxyethylenealkyl ethers such as Cetomacrogol™ 1000. Surfactants are desirably addedto both of the inner oil phase and the outer water phase so as toprepare a stable emulsion.

[0038] Co-surfactants suitable for creams of the present inventionpreferably include higher alcohols, especially stearyl alcohol, cetylalcohol or a mixture of both, i.e. cetostearly alcohol.

[0039] In order to maintain stability of the emulsion and enhance theskin transfer rate of the active ingredient, the total concentration ofsurfactants and co-surfactants is preferably within the range of from 2to 7% by weight. A stable emulsion was obtained when the ratio betweensurfactants and co-surfactants was within the range of from 1:1 to 1:11,more preferably 1:4.

[0040] Base materials for the oil phase of O/W creams includepetrolatum, liquid paraffin, wax or the like. During addition ofmaxacalcitol to the oil phase, it is convenient to use a solubilizer orsolvent promoter suitable for facilitating dissolution of maxacalcitol.Oil phase can be prepared by, for example, first dissolving maxacalcitolin a solvent promoter such as ethanol, then adding the solution to asolubilizer such as middle chain fatty acid triglyceride (MCT) andfinally adding the resulting mixture to a base material such aspetrolatum as mentioned above.

[0041] Suitable solubilizers other than middle chain fatty acidtriglyceride (MCT) include isopropyl myristate, diisopropyl adipate, andtriacetin.

[0042] The water phase of O/W type creams may optionally containsurfactants and can be adjusted to a desired pH with an appropriatebutter (PBS or the like).

[0043] Oil and water phase may appropriately contain preservatives (suchas methylparaben) or the like.

[0044] (2) Maxacalcitol Exists in the Water Phase

[0045] Maxacalcitol can be effectively dispersed in the outer waterphase either by homogeneously dispersing a maxacalcitol stock pulverizedby a jet mill or the like or dissolving maxacalcitol in an organicsolvent such as ethanol and then homogeneously dispersing the solutionin the outer water phase.

[0046] Maxacalcitol is not stable in aqueous solutions and thereforesimply dispersing it after pulverization or simply dispersing it as asolution in ethanol or the like is sometimes insufficient to maintainits heat stability. Thus, an alcohol and/or a nonionic surfactant may beassed to the outer water phase for the purpose of improving heatstability of maxacalcitol. As a result, not only heat stability but alsoskin transfer of maxacalcitol can be controlled.

[0047] Alcohols that can be added to the outer water phase includemonohydric alcohols or dihydric alcohols. Preferred monohydric alcoholsinclude ethanol, and preferred dihydric alcohols include glycols, amongwhich propylene glycol and 1,3-butylene glycol are especially preferred.

[0048] Nonionic surfactants that can be added to the outer water phasepreferably include ether-type surfactants, especially polyoxyethylenealkyl ethers and Pluronic™-type surfactants. Specific examples ofnonionic surfactants include Cetomacrogol 1000.

[0049] When maxacalcitol is contained as an active ingredient in thewater phase of O/W type creams of the present invention, the water phasecan be adjusted to a desired pH using an appropriate buffer (such asPBS).

[0050] Base materials for the oil phase of O/W type creams includePetrolatum, liquid paraffin and wax.

[0051] Oil and water phases may further contains surfactants and/orco-surfactants for the purpose of obtaining a stable emulsion.

[0052] Examples of surfactants existing in the oil phase preferablyinclude ether-type surfactants, particularly polyoxyethylene alkylethers such as Cetomacrogol 1000.

[0053] Examples of co-surfactants existing in the oil phase preferablyinclude higher alcohols, especially stearyl alcohol, cetyl alcohol or amixture of both, i.e. cetostearyl alcohol.

[0054] The total concentration of surfactants and co-surfactants is notspecifically limited in the present invention and can be appropriatelycontrolled, but typically within the range of from 2 to 7% by weight.The ratio between surfactants and co-surfactants is not specificallylimited either in the present invention, but typically within the rangeof from 1:1 to 1:11, preferably 1:4.

[0055] The oil and water phases may appropriately contain preservatives(such as methylparaben) or the like.

[0056] The proportion of the oil phase in O/W type creams (whereinmaxacalcitol exists in the oil or water phase) can be appropriatelyselected, but preferably 30-50% by weight, most preferably about 40% byweight.

[0057] Creams of the present invention can be used to treat variouscases of psoriasis such as psoriasis vulgaris, psoriasis pustulosa,psoriasis guttata, erythroderma psoriaticum, psoriasis arthropathica andpsoriasis gravis. The dose depends on the condition of the disease orother factors, but preferably a cream containing 2 μg/g to 100 μg/g ofmaxacalcitol is administered once to several times per day.

[0058] The following examples further illustrate the present inventionwithout limiting the same thereto.

EXAMPLES

[0059] Preparation Example A-1

[0060] The oil phase components and water phase components shown in thefollowing Formulation example A-1 were dissolved on an oil bath at 75°C.-80° C. The content of maxacalcitol in the whole cream was 50 μg/g,the concentration of cetostearyl alcohol was 7.2% by weight and theconcentration of Cetomacrogol 1000 was 1.8% by weight.

Formulation Example A-1

[0061] Amount Oil phase components Maxacalcitol 5.0 mg Ethanol 50 μl MCT1.0 g Cetostearyl alcohol 7.2 g Cetomacrogol 1000 1.8 g Methylparaben0.04 g White Petrolatum Adjusted to 40.0 g in total Water phasecomponents Cetomacrogol 1000 0.02 g Methylparaben 0.04 g PBS (25 mM, pH8.0) Adjusted to 60.0 g in total

[0062] The oil phase components and water phase components were mixedand stirred by a homomixer and a paddle mixer while the temperature wasmaintained at 75° C. to 80° C. The homomixer was stopped and the mixturewas cooled with stirring by the paddle mixer to give the desired cream.

Preparation Example A-2

[0063] A cream was prepared by the same procedure as in Preparationexample A-1 except that the concentrations of maxacalcitol, cetostearylalcohol and Cetomacrogol 1000 were 50 μg/g, 5% by weight and 1.25% byweight, respectively.

Preparation Example A-3

[0064] A cream was prepared by the same procedure as in Preparationexample A-1 except that the concentrations of maxacalcitol, cetostearylalcohol and Cetomacrogol 1000 were 50 μg/g, 4% by weight and 1% byweight, respectively.

Preparation Example A-4

[0065] A cream was prepared by the same procedure as in Preparationexample A-1 except that the concentrations of maxacalcitol, cetostearylalcohol and Cetomacrogol 1000 were 50 μg/g 3% by weight and 0.75% byweight, respectively.

[0066] Test Example A-1 (Skin Absorption Test)

[0067] Each of the creams obtained in the above Preparation examples A-1to A-5 was applied on the dorsal skin of 7-week old male SD rats and therate of maxacalcitol left on the skin and the level of maxacalcitol inthe skin were determined 4 hours after the application.

[0068] Rats were maintained at a constant temperature and a constanthumidity with solid diet and water in vitae, and cervicodorsally shavedwith an electric clipper and a shaver on the day before administration.On the test day, a 4×3 cm plastic frames was fixed on the shaved portionof the skin under ether anesthesia and 15 μg of maxacalcitol/0.3 gcream/kg was applied to exactly within that portion of the skin with aspatula or the like. After 4 hours, the cream was wiped off with 3pieces of absorbent cotton soaked in 70% ethanol and assayed for theamount of maxacalcitol left on the skin. After completion of wiping, a3×4 cm skin section was cut out from the treated site and assayed forthe amount of maxacalcitol in the skin.

[0069] The results are shown in FIG. 1.

Test Example A-2 (Stability Test)

[0070] The creams of Preparation examples A2-A5 were evaluated forphysical and chemical stability. Vials charged with the creams wereaccelerated in an incubator and samples over time. The resulting creamswere observed with the naked eye to evaluate the emulsification state;the maxacalcitol content in the creams was measured to evaluate therates of residual maxacalitol tot he initial amount.

[0071] The results are shown in Table 1. TABLE 1 Preparation examplesA-5 A-4 A-3 A-2 Cetostearyl alcohol 2% 3% 4% 5% Initial (%) 100 100 100100 80° C., 1 week (%) 83.21# 83.11# 84.47# 82.94# 80° C., 2 weeks (%)60.44# 60.63# 69.76# 63.82# 80° C., 3 weeks (%) 44.94# 46.36# 54.51#40.99# 60° C., 2 weeks (%) 96.27# 94.83# 94.88# 91.98# 60° C., 4 weeks(%) 94.06# 93.66# 94.78# 91.76# 60° C., 3 months (%) 73.21# 79.40#81.59# 75.22# 50° C., 2 weeks (%) # 99.61# 99.22# # 50° C., 4 weeks (%)96.38# 101.53#  100.77#  95.67# 40° C., 4 weeks (%) 97.14# 98.99  98.90 95.77  40° C., 3 months (%) 95.13# 96.21  96.64  97.32 

[0072] Desirable creams should have high skin absorption, high drugutilization and high storage stability. As an initial stage, aformulation similar to existing commercially available creams wasemployed (Preparation example A-1), revealing such low skin-absorptionthat further improvement in adsorption seemed necessary. The lowabsorption was believed to be attributable to 1) high affinity ofmaxacalcitol for the oil phase base material, 2) low delivery orprobability of access of the oil phase to skin, and 3) inhibition ofrelease of the maxacalcitol from the oil phase during maxacalitoltransfer to skin, so that the formulation was modified to be improved inthese factors.

[0073] As measured to deal with these factors 1), 2) and 3), we decidedto decrease the amount of the cosolubilizer MCT, increase the proportionof oil phase and decrease the surfactant concentration at the oil/waterinterface and around oil phase particles, respectively. In order tomaintain an emulsion form in O/W type creams, at least 2% of cetostearylalcohol was required in a preparation and the most preferredconcentration of Cetomacrogol 1000 in that case was 0.5%, whichcorresponds to ¼ of the concentration of cetostearyl alcohol(preparation example A-5; all the emulsifier concentrations mentionedhereinbelow are the concentrations of cetostearyl alcohol and theconcentrations of Cetomacrogol 1000 are ¼ of those concentrations unlessotherwise specified).

[0074] A cream having the lowest possible emulsifier concentration in sofar as an emulsion could be maintained was evaluated for skin absorptionand physical and chemical stability (FIG. 1 and Table 1). In the creamhaving a decreased emulsifier concentration, skin absorption wasimproved, however phase separation occurred at week 2 at 40° C. whichevidenced low physical stability. Under microscopic observation, oilphase particles of this cream had larger diameters and widerparticle-size-distribution as compared with those in creams having highemulsification stability; also observed were fine particle masses whichwere presumably petrolatum; these data indicated that the emulsifierconcentration was too low to achieve complete emulsification.

[0075] Considering that establishing a stable emulsion by increasing theemulsifier is essential to ensure high physical stability, we selectedcreams having emulsifier concentrations which were increased to 3%-5%(Preparation examples A-2 to A-4) and evaluated them for skin absorptionand physical and chemical stability (FIG. 1 and Table 1). Formulationshaving cetostearyl alcohol concentrations of 3% to 5% showed higher skintransfer rates than that of the initial formulation. However, the skintransfer rates were comparable and independent of the emulsifierconcentration in the tested range. As is apparent from Table 1, theseformulations did now show the phase separation in the early stage, whichphase separation had occurred at the cetostearyl alcohol concentrationof 2%; their improved physical stability was apparent. As to chemicalstability, the creams with cetostearyl alcohol concentrations of 3% ormore showed high residual rates of maxacalcitol at cetostearyl alcoholconcentrations of 3% to 5%, suggesting that they all can be stored atroom temperature; in fact the cream with a cetostearyl alcoholconcentration of 4% was considered to be most preferable because it wasmost stable at higher temperature.

Preparation Example B-1

[0076] The oil phase components and the water phase components (exceptfor maxacalcitol) that are shown in the following Formulation exampleB-1 were dissolved in an oil bath at 75° C. to 80° C. The concentrationof cetostearyl alcohol in this case was 4.0% by weight and theconcentration of Cetomacrogol 1000 was 1.0 by weight. The two phasecomponents were mixed and stirred by a homomixer and a paddle mixerwhile the temperature was maintained at 75° C. to 80° C. The homomixerwas stopped and the mixture was cooled with stirring by the paddle mixerto give a cream. The resulting cream was combined with a solution ofmaxacalcitol in ethanol and the mixture was stirred to homogeneity.

Formulation Exmaple B-1

[0077] Oil Phase MCT (middle chain fatty acid 1.0 g triglyceride)Cetostearyl alcohol 4.0 g Cetomacrogol 1000 1.0 g Methylparaben 0.04 gWhite petrolatum Adjusted to 40.0 g in total Water phase Cetomacrogol0.02 g Methylparaben 0.04 g PBS (25 mM, pH 8.0) to 60.0 g Maxacalcitol5.0 mg Ethanol 50μ

Comparison Example B-1

[0078] For comparison, oil phase components and water phase componentsshown in the following Comparison formulation example B-1 were dissolvedon an oil bath at 75° C. to 80° C. in this Comparison formulationexample B-1, the active ingredient maxacalcitol exists in the oil phase.The oil and water phases were mixed and stirred by a homomixer and apaddle mixer while the temperature was maintained at 75° C. to 80° C.The homomixer was stopped and the mixture was cooled with stirring bythe paddle mixer to give a cream. Comparison formulation example B-1(Comparison example) Oil phase Maxacalcitol/Ethanol 5.0 mg/50 μl MCT(middle chain fatty acid 1.0 g triglyceride) Cetostearyl alcohol 4.0 gCetomacrogol 1000 1.0 g Methylparaben 0.04 g White petrolatum Adjustedto 40.0 g in total Water phase Cetomacrogol 1000 0.02 g Methylparaben0.04 g PBS (25 mM, pH 8.0) Adjusted to 60.0 g in total

Test Example B-1

[0079] The creams obtained in the above Preparation example B-1 andComparison example B-1 were evaluated for skin transfer, physicalstability and chemical stability.

[0080] For evaluation of skin transfer, rats were maintained at aconstant temperature and a constant humidity with solid diet and waterin vitae, and cervicodorsally shaved with an electric clipper and ashaver on the day before administration. On the test day, 1 4×3 cmplastic frame was fixed on the shaved portion of the skin under etheranesthesia and 15 μg of maxacalcitol/0.3 g cream/kg was applied toexactly within that portion of the skin with a spatula or the like.After 4 hours, the applied cream was wiped off with 3 pieces ofabsorbent cotton soaked in 70% ethanol and assayed for the amount ofmaxacalcitol left on the skin.

[0081] For evaluation of stability, vials charged with the creams weremaintained in an incubator and sampled at predetermined times. Theresulting creams were observed with the naked eye to evaluate theemulsification state; the maxacalcitol content in the creams wasmeasured to evaluate the rates of residual maxacalcitol to the initialamount.

[0082] The results are shown in Table 2. TABLE 2 Formulation example B-Comparison formulation 1 example B-1 Unabsorbed rate 62.1% (n = 3) 81.9%(n = 7) after 4 hours Storage stability 95.6 (25° C., 6 months) 96.6%(40° C., 3 months)

[0083] As compared with the cream containing maxacalcitol in the inneroil phase (Comparison formulation example B-1), the cream having thesame formulation but containing maxacalcitol in the outer water phaseshowed excellent improvement in skin transfer rate, which doubled toapproximately 40% in 4 hours as shown in Table 2. It also showed highstorage stability of 95.6% at 25° C. after 6 months, but furtherimprovement was desired.

Preparation Example B-2

[0084] The oil phase components and the water phase components (exceptfor maxacalcitol) that are shown in the following Formulation exampleB-2 were dissolved in an oil bath at 75° C. to 80° C. The concentrationof cetostearyl alcohol was 4.0% by weight and the concentration ofCetomacrogol 1000 was 1.0% by weight. The two phase components weremixed and stirred by a homomixer and a paddle mixer while thetemperature was maintained at 75° C. to 80° C. The homomixer was stoppedand the mixture was cooled with stirring by the paddle mixer to give acream. The resulting cream was combined with a solution of maxacalcitolin ethanol and the mixture was stirred to homogeneity.

[0085] Maxacalcitol is known to be unstable in aqueous solutions. Thecream of Preparation example B-1 is also somewhat defective in chemicalstability. However, as shown in Formulation example B-2, by addingalcohols or glycols to the water phase, the chemical stability can bedramatically improved, for example, by a factor of several dozenswithout affecting skin transfer rate. These properties can be controlledby changing the proportions of glycols.

Formulation Example B-2

[0086] Oil phase MCT (middle chain fatty acid 1.0 g triglyceride)Cetostearyl alcohol 4.0 g Cetomacrogol 1000 1.0 g Methylparaben 0.04 gWhite petrolatum Adjusted to 40.0 g in total Water phase Cetomacrogol1000 0.02 g Methylparaben 0.04 g Propylene glycol 30.0 g Butylene glycol12.0 g PBS (25 mM, pH 8.0) To 60.0 g Maxacalcitol 5.0 mg Ethanol 50 μl

INDUSTRIAL APPLICABILITY

[0087] In O/W type creams of the present invention, high physical andchemical stability and improved skin transfer rate of maxacalcitol wereachieved by modifying the elulsifier concentration, oil/water ratio orthe like in the formulations or by suitably incorporating maxacalcitolin the water phase. According to the present invention, therefore,excellent preparations showing improved skin transfer and heat stabilityof the active ingredient can be simultaneously developed.

What is claimed is:
 1. An O/W cream comprising maxacalcitol as an activeingredient, wherein said maxacalcitol is present in both the oil phaseand in the water phase.
 2. The O/W cream according to claim 1 furthercomprising an emulsifier.
 3. The O/W cream according to claim 2 whereinthe emulsifier is a mixture of a surfactant and a cosurfactant.
 4. TheO/W cream according to claim 3 wherein the ratio between the surfactantand the cosurfactant is within the range of from 1:1 to 1:11.
 5. The O/Wcream according to claim 3 wherein the total concentration of thesurfactant and the cosurfactant is within the range of from 2% by weightto 7% by weight.
 6. The O/W cream according to claim 3 wherein thesurfactant is an ether.
 7. The O/W cream according to claim 6 whereinthe ether is a polyoxyethylene alkyl ether.
 8. The O/W cream accordingto claim 4 wherein the surfactant is an ether.
 9. The O/W creamaccording to claim 8 wherein the ether is a polyoxyethylene ether. 10.The O/W cream according to claim 3 wherein the cosurfactant is a higheralcohol.
 11. The O/W cream according to claim 10 wherein the higheralcohol is stearyl alcohol, cetyl alcohol, or cetostearyl alcohol. 12.The O/W cream according to claim 4 wherein the cosurfactant is a higheralcohol.
 13. The O/W cream according to claim 12 wherein the higheralcohol is stearyl alcohol, cetyl alcohol, or cetostearyl alcohol. 14.The O/W cream according to claim 2 wherein the proportion of the oilphase in the O/W cream is within the range of from 30% by weight to 50%by weight.
 15. The O/W cream according to claim 1 wherein themaxacalcitol present in the water phase is crystalline maxacalcitolwhich has been pulverized.
 16. The O/W cream according to claim 1wherein the maxacalcitol present in the water phase is dissolved in anorganic solvent.
 17. The O/W cream according to claim 1 wherein themaxacalcitol present in the water phase is present along with at leastone of an alcohol and a nonionic surfactant.